Pharmaceutical manufacturers are continuously attempting to improve methods for delivering drugs to enhance and sustain their effects in human therapy. A significant development in drug delivery systems occurred in 1972 with the development of osmotic delivery systems as described by U.S. Pat. Nos. 3,845,770 and 3,916,899. Modifications to the rate-controlling osmotic delivery systems of the prior art are also disclosed in U.S. Pat. Nos. 4,816,263 and 4,902,514.
Such modified osmotic delivery systems use a semi-permeable wall to surround an interior containing the drug to be delivered. The external wall is permeable to the passage of an external fluid and may not be permeable to the drug. Such systems may include at least one outlet in the wall for delivering the drug through the osmotic system. The systems operate by absorbing gastric fluid through the semi-permeable wall into the interior of the dosage form at a rate determined by the permeability of the semi-permeable wall and the osmotic pressure gradient across the semi-permeable wall. The absorbed fluid produces an aqueous solution containing the drug that is then delivered to the body through at least one opening in the wall.
U.S. Pat. No. 4,816,263 discloses an osmotic device form for delivering isradipine to a biological receptor site in a rate-controlled amount over a prolonged period for cardiovascular therapy. The pharmaceutical dosage form adapted, designed, and shaped as an osmotic drug delivery system is manufactured by wet granulation and includes two compositions which form a bi-layered tablet coated by a semi-permeable wall. The first composition includes the drug and contains polyethylene oxide having a molecular weight of 200,000 which is screened through a 40 mesh screen. Specific amounts of isradipine and hydroxypropyl methylcellulose having a molecular weight of 11,200 are added to the polyethylene oxide and slowly mixed with denatured, anhydrous ethanol using a conventional mixer. The wet granulation formed is then passed through a 20 mesh screen, dried at room temperature and passed through the 20 mesh screen again. Magnesium stearate is then added to the granulation and mixed in a roller mill.
The second composition used in the osmotic device is prepared by mixing polyethylene oxide of molecular weight 7,500,000 with sodium chloride in a blender to form a homogeneous blend. The blend is passed through a 40 mesh screen. The mixture is then mixed with a specific amount of hydroxypropyl methylcellulose having a molecular weight of 11,200 and with a specific weight of ferric oxide. Denatured, anhydrous ethanol is slowly added to the blended mixture while mixing again before the wet granulation is screened through a 20 mesh screen. A bi-layered press is used to compress the granulation into two-layered tablets. The tablet is surrounded with a semipermeable wall including 97% cellulose acetate and 3% polyethylene glycol of molecular weight of 3,350. The wall forming composition is dissolved in methylene chloride and methanol to make a 4% solids solution. The wall forming composition is sprayed onto and around the bilaminate in an Aeromatic Air Suspension Coater. The coated tablet is then dried. A 25 mm exit orifice is laser drilled on the laminate side of the osmotic device.
A dosage form for delivering and administering nilvadipine for treating cardiovascular symptoms in a rate-controlled dose over a period of time was developed as described in U.S. Pat. No. 4,902,514. This patent is directed to providing a dosage form manufactured as an osmotic agent that substantially reduces and/or eliminates the unwanted influence of the gastrointestinal environment and still provides controlled administration of nilvadipine over time. The device includes an insoluble coating enclosing the interior within the dosage form. The coating of the dosage form is permeable to the inward passage of exterior fluid present in the gastrointestinal tract into the interior of the dosage form.
In 1987, Urquhart et al. developed an extended-release drug delivery system for delivering a quantity of tiny pills to the gastrointestinal tract. The system includes a pharmaceutical oral capsule prepared with a drug carrier formed of an aqueous polymer and oil capable of controlling the rate of transit of the capsule and the release of the drug from the capsule to the gastrointestinal tract.
Products formulated for controlled-release are generally described as sustained release, prolonged action, depot, repository, delayed-action, retarded-release, and timed-release. Drug products which are formulated for prolonging absorption include dosage forms for oral, injectable and topical use as well as suppositories for insertion in the body cavities. Extended-release tablets are defined herein as pharmaceutical solid dosage forms containing drug substances which are released from the tablet or delivery system over an extended period of time using specific ingredients and includes mechanisms as discussed above such as timed-release, intermittent release and retarded release. They are produced by compression of a formulation containing the drug and certain excipients selected to aid in the processing and release of the drugs. Excipients are classified in accordance with their intended function. Exemplary components for such formulations include fillers, binders, lubricants, and glidants. Without excipients, most drugs and pharmaceutical components cannot be directly compressed into tablets primarily due to the poor flow and/or cohesive properties of most drugs. Extended-release tablets may be coated or uncoated, and are generally formed of powdered, crystalline materials.
Drugs can be administered from a delivery system that releases the drug as it passes through the gastrointestinal tract. Extended-release delivery systems are used because they eliminate the need for multiple dosing. The convenience of extended-release preparations which maintain the blood concentration of the drug at a desired level over a prolonged period of time has been recognized. Extended-release preparations such as a slow-release matrix type tablet in which the ingredients are embedded in a matrix, such as polymeric resins, release the active ingredient by diffusion and erosion.
Most extended-release forms are designed so that the administration of a single dosage unit provides the immediate release of an amount of drug that promptly produces the desired therapeutic effect as well as a gradual and continual release of additional amounts of drug to maintain this level of effect over an extended period of time. In this type of dosage form, the design is based on the particular qualities of each individual drug.
What may be an effective type of dosage form design for one drug may be ineffective in promoting the extended-release of another drug because of peculiar physical, chemical and biological qualities of the different drugs. To maintain a constant level of drug in the system, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.
Other advantages of extended-release products are reduced side effects and increased patient convenience. These advantages relate to the fact that extended-release preparations maintain the blood concentration of the drug at a desired level over a prolonged period of time which allows patients to reduce the frequency of dosing. This is considered an advantage in ensuring patient compliance in taking medication. Patients required to take one or two dosage units a day are less likely to forget their medication than if they are required to take their medications three or four times a day.
Therefore, there is a need in the art for a drug delivery system that has a sufficiently long transit time in the stomach and acts as an in vivo reservoir, and which releases the drug at a controlled rate and continuously over a prolonged period of time for absorption in the stomach and the intestine.
The method of preparation and type of excipients used in making such dosage forms must be carefully selected to give the formulation the desired physical characteristics that allow for rapid compression of tablets. After compression, the tablets must have a number of additional attributes such as appearance, hardness, and an acceptable dissolution profile. Choice of fillers and other excipients will depend on the chemical and physical properties of the drug, behavior of the mixture during processing, and the properties of the final tablets. Such determinations are typically done by preformulation studies which determine the physical and chemical compatibility of the active component with the proposed excipients. The properties of the drug, its dosage forms and the economics of the process will determine selection of the best process for tableting. Generally, both wet granulation together with direct compression are used in developing a tablet.
The wet granulation method is used to convert a powder mixture into granules having suitable flow and cohesive properties for tableting. The procedure includes mixing the powders in a suitable blender followed by adding a granulating solution under shear to the mixed powders to obtain a granulation. The damp mass is then screened through a suitable screen and dried by tray drying or fluidized bed drying. Alternately, the wet mass may be dried and passed through a mill. The overall process includes: weighing, dry powder blending, wet granulating, drying, milling, blending, lubrication, and compression.
In general, powdered formulations do not have sufficient adhesive or cohesive properties to form strong granules. A binder is usually required to bind the powder particles together due to the poor cohesive properties of most powders. In addition, when processing heat- and moisture-sensitive drugs further precautions must be taken and standard wet granulation methods must be modified to accommodate such drugs. A large number of processing steps are required in tableting moisture- and/or heat-sensitive drugs, and the processes are very time and labor intensive, which increases manufacturing costs. While wet granulation offers the advantage of improving cohesiveness for tableting, it has also been known to reduce the compressibility of some pharmaceutical excipients, such as microcrystalline cellulose.
Direct compression is regarded as a relatively quick process in which the powdered materials are directly compressed without changing the physical and chemical properties of the drug. The active ingredient, direct compression excipients, and other auxiliary substances, such as glidants and lubricants, are blended in a twin-shell or similar blending apparatus before being compressed into tablets. This type of mixing is generally preferred in preparing pharmaceutically acceptable dosage forms. In addition, Remington's Pharmaceutical Sciences (RPS), 17th ed. (1985) states that the manner in which a lubricant is added to a formulation must be carefully controlled. As a result, lubricants may be added to a granulation by gentle mixing. This avoids negative effects on the hardness and disintegration properties of the tablets which can be caused by prolonged blending of a lubricant with a granulation. Similarly, Ansel et al., Pharmaceutical Dosage Forms And Drug Delivery Systems, 6th ed. (1995) pp. 199, 213-220 indicates that excessive blending of lubricants with a granulation can cause waterproofing of the granule and reduce the tablet hardness or strength of the compressed tablet. For these reasons, high shear mixing conditions are generally not used to blend lubricants.
Pharmaceutical manufacturers prefer use of direct compression techniques to wet and dry granulation methods because of the lower processing time and the cost advantages. However, direct compression is generally limited to those situations in which the drug or active ingredient has a crystalline structure and physical characteristics required to form pharmaceutically acceptable tablets.
Some active ingredients which do not themselves have the necessary properties for direct compression, can be formed into a directly compressible formulation by incorporating one or more excipients before using direct compression. However, effective excipients for drugs vary with the drug and its properties. As a result, determination of an acceptable combination of excipients which are compatible with each other and with one particular drug, and which are effective for rendering that drug with the excipients compressible would not necessarily operate to render another drug directly compressible into an acceptable dosage form. In addition, each excipient added to the formulation will contribute to increasing the tablet size of the final product. Because tablet size must be within acceptable parameters, there is a limit beyond which increasing tablet size to accommodate additional or increased amounts of excipients to enhance compressibility is not practical. As a result, manufacturers are often limited to using the direct compression method for those formulations which contain a low dose of the active ingredient per compressed tablet such that the formulation may accommodate sufficient excipients to make direct compression practical.
An example of the inability to directly compress a drug can be found with reference to acetaminophen. In U.S. Pat. No. 5,733,578, acetaminophen could not be directly compressed in a formulation including microcrystalline cellulose to form acceptable tablets. The final product tended to be soft, prone to capping, i.e., delamination of one or more of the tablet faces, and was otherwise not pharmaceutically acceptable in that the resulting tablets were so large they would be difficult to swallow. As a result, that patent relied on a time consuming and expensive wet granulation technique for compression of acetaminophen.
U.S. Pat. No. 4,661,521 is also directed to the tableting of acetaminophen, and attempts to use direct compression techniques. However, the acetaminophen could only be directly compressed by including the additional steps of slugging or roller compaction of the tableting mix. In that patent, a fluidized bed apparatus was used for thorough blending of acetaminophen with pregelatinized starch. High shear mixing was used to form a slurry which was fluidized and dried before sizing to achieve the appropriate particle size.
One of the disadvantages of direct compression as a method of tablet manufacturing is the potential size of the compressed tablets. If the amount of active ingredient is high, a pharmaceutical formulator may choose to wet granulate the active ingredient with other excipients to achieve an acceptable tablet size which includes the desired amount of drug. Wet granulation requires less filler, binder, and other excipients than direct compression, because the process of wet granulation contributes toward the desired physical properties, including the compressibility, of the tablet.
Despite the advantages of direct compression, such as reduced processing time and cost, wet granulation is widely used in the industry to prepare solid dosage forms. Wet granulation is often preferred over direct compression, because wet granulation has a greater chance of overcoming any problems associated with the physical characteristics of various ingredients in the formulation. This provides material which has the required flow and cohesive properties necessary to obtain an acceptable dosage form without overloading the tablet formulation with large amounts of excipients.
The popularity of wet granulation over direct compression is based on at least three advantages, in addition to tablet size as discussed above. First, wet granulation provides the material to be compressed with better wetting properties, particularly so in the case of hydrophobic drugs. The addition of hydrophilic excipients makes the surface of the hydrophobic drug more hydrophilic, which reduces disintegration and dissolution problems. Second, the content uniformity of the solid dosage form is generally improved with wet granulation because all of the granules usually contain the same amount of drug. It is important that the particular components of the formulation for a given tablet be consistent to satisfy the necessary quality standards and legal criteria applicable for tablet manufacture, sale and usage. Lastly, the segregation of an active ingredient from excipients is avoided.
Segregation presents a problem in direct compression. The size and shape of particles including the granulate to be compressed are optimized using wet granulation processes. This is because when a dry solid is wet granulated, the binder "glues" particles together and they agglomerate into spherical granules. In direct compression, such granules are not formed and particles of differing size and shape tend to segregate in the blended formulation.
1-(3-chlorophenyl)-2-[(1,1,-dimethylethyl)amino]-1-propanone hydrochloride, referred to herein by its common name of bupropion hydrochloride, an antidepressant, is considered a moderate dose drug. Most tablet formulations include a range of 30-40% by weight of bupropion hydrochloride per tablet. This relatively moderate dose drug, combined with its rather poor physical characteristics for direct compression, has not allowed pharmaceutical manufacturers to use direct compression as a method to prepare the final tablet. Bupropion hydrochloride has poor compressibility and relatively high solubility. The high solubility (about 312 mg/ml (the Merck Index, 12th ed., pp. 246-247)) in aqueous and biological fluids, makes it very difficult to deliver bupropion hydrochloride in any meaningful amounts to biological receptor sites over time. As such, it is essential to control the release rate of bupropion hydrochloride in order to extend its absorption over time. Bupropion hydrochloride is also very hygroscopic and susceptible to decomposition, thereby presenting stability problems. Because of these properties, most manufacturers produce bupropion hydrochloride using the wet granulation method.
In spite of the advantages achieved by wet granulation in tableting bupropion hydrochloride, it would be very advantageous to have a method for the direct compression of tablets having the appropriate dose of bupropion hydrochloride. There is a need in the art for techniques and a formulation including a particular combination of pharmaceutical excipients which would allow for preparation of a specific dose of bupropion hydrochloride tablets by direct compression to avoid the time and expense involved with manufacturing using wet granulation techniques.
In addition to a need for an improved, more economical tableting process for bupropion hydrochloride, a dosage form is needed which provides for improved extended-release delivery of the drug. Due to the relatively high solubility of bupropion hydrochloride in aqueous and biological fluids as well as its susceptibility to decomposition, it is imperative that the release be controlled in order to increase the drug's therapeutic effectiveness. As such, in developing a more economical process for bupropion hydrochloride, care must be taken to ensure that the release profile is at least comparable to, if not better than, release rates achieved by tablets which are formed in accordance with existing wet granulation tableting methods.